B cells represent a critical component of the immune system: in the absence of these cells, the ability to fight infections and to establish long-term protective immunity are severely impaired. B cell development and function depend on elaborate mechanisms that tightly control gene expression and the physiologic breakage and repair of DNA that occurs uniquely in lymphoid cells. Although these mechanism function with remarkable fidelity, they can be perturbed by discrete genetic lesions, leading to immune dysfunction or lymphocytic cancers in humans. Thus, dissecting the molecular pathways that control B cell development and function is critical to advancing our understanding of diseases that arise from the immune system. The overarching objective of our proposal is to gain new insight into the mechanisms that globally control gene expression during B cell development. It has been established that a transcription factor network formed by several DNA-binding proteins is primarily responsible for regulating gene transcription and immunoglobulin gene rearrangement during B cell development. Yet, the pathways that connect these key events to the B cell transcription factor network have only begun to be explored. In our previous studies, we identified a novel mutant mouse strain named Justy (for just T cells), which carries a recessive mutation that abolishes B cell development but does not impair other major aspects of mouse physiology. The causative lesion is a point mutation that dramatically reduces, but does not abolish, expression of a protein called Gon4-like, which contains homology to factors that mediate epigenetic regulation of gene transcription. Gene expression profiling indicated that decreased Gon4-like expression does not impair activation of B-lineage genes, but does prevent the repression of genes encoding proteins that antagonize B cell development. In addition, DNA recombination in the immunoglobulin heavy chain locus is impaired by the mutation. Lastly, roughly half of Justy mice that reach 1 year of age develop some form of lymphoid neoplasia. Based on these data, we hypothesize that Gon4-like is a critical component of the transcription factor network that regulates gene expression and immunoglobulin gene recombination during B cell development. We propose to create and characterize alternative genetic models for Gon4-like deficiency to define the physiologic role of this gene in the mouse and its importance throughout the B lineage. In addition, we will use cell culture systems, retroviral gene transfer technology and methods for quantifying gene expression as tools for integrating Gon4-like into the regulatory circuitry the controls B cell development and immunoglobulin gene rearrangement. To complement these studies, we will use a combination of molecular and biochemical methodologies to define co-factors for Gon4-like and to determine its role in gene regulation at the genome level. Completion of these studies will break new ground in our understanding of the mechanisms that control B cell development. Further, the knowledge gained will provide new insights regarding the fundamental processes that contribute to immune dysfunction or the development of lymphoid cancers.